1. Field of the Invention
The present invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the present invention relates to compounds that are new ester derivatives, methods of preparing such compounds, compositions containing such compounds, and therapeutic uses of such compounds.
2. Discussion of the Background
Airway obstruction characterizes a number of sever respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). Events leading to airway obstruction include oedema of airway walls, increased mucous production and inflammation.
Drugs for treating respiratory diseases such as asthma and COPD are currently administered through inhalation. One of the advantages of the inhalatory route over the systemic one is the possibility of delivering the drug directly at the site of action, avoiding any systemic side-effects, thus resulting in a more rapid clinical response and a higher therapeutic ratio.
Inhaled corticosteroids are the current maintenance therapy of choice for asthma and together with bronchodilator beta2-agonists for acute symptom relief, they form the mainstay of current therapy for the disease. The current management of COPD is largely symptomatic by means of bronchodilating therapy with inhaled anticholinergics and inhaled beta2-adrenoceptor agonists. However, corticosteroids do not reduce the inflammatory response in COPD as they do in asthma.
Another class of therapeutic agents which has been widely investigated in view of its anti-inflammatory effects for the treatment of inflammatory respiratory diseases such as asthma and COPD is represented by the inhibitors of the enzymes phosphodiesterases (PDEs), in particular of the phosphodiesterase type 4 (hereinafter referred to as PDE4).
Various compounds acting as PDE4 inhibitors have been disclosed in the prior art. However, the usefulness of several PDE4 inhibitors of the first-generation such as rolipram and piclamilast has been limited due to their undesirable side effects. Said effects include nausea and emesis due to their action on PDE4 in the central nervous system and gastric acid secretion due to the action on PDE4 in parietal cells in the gut.
The cause of said side effects has been widely investigated.
It has been reported that PDE4 exists in two distinct forms representing different conformations, that were designated as high affinity rolipram binding site or HPDE4, especially present in the central nervous system and in parietal cells, and low affinity rolipram binding site or LPDE4 (see, Jacobitz, S et al., Mol. Pharmacol., 1996, 50, 891-899), which is found in the immune and inflammatory cells. While both forms appear to exhibit catalytic activity, they differ with respect to their sensitivity to inhibitors. In particular, compounds with higher affinity for LPDE4 appear less prone to induce side-effects such as nausea, emesis and increased gastric secretion.
The effort of targeting LPDE4 has resulted in a slight improvement in the selectivity for the second-generation PDE4 inhibitors such as cilomilast and roflumilast. However, even these compounds are not provided with a good selectivity towards LPDE4.
In fact, according to the literature (Giembycz M A et al., Expert Opin. Investg. Drugs, 2001; 10:1361-1379) cilomilast has an affinity toward HPDE4 comparable to that toward LPDE4, after oral administration (HPDE4 IC50=120 nM; LPDE4 IC50=90 nM; HPDE4/LPDE4 ratio about 1.3).
Other classes of compounds acting as PDE4 inhibitors have been disclosed in the prior art. For example, WO 9402465 discloses, among others, ketone derivatives of general formula
wherein R1 is lower alkyl and R2 may be alkyl, alkenyl, cycloalkyl, cycloalkyl, cycloalkenyl, cyclothioalkyl or cyclothioalkenyl.
WO 95/35281 concerns tri-substituted phenyl derivatives generically belonging to the classes of ethers and enolethers.
WO 2006/064355 concerns heterocyclic compounds useful for the treatment of inflammatory and allergic disorders.
Although several PDE4 inhibitors have been disclosed so far, there is still a need for more efficacious and better tolerated compounds. In particular it would be highly advantageous to provide more selective compounds, e.g. endowed with a higher affinity toward the LPDE4 in comparison to HPDE4, in order to attenuate or avoid the side effects associated with its inhibition.